Environmental exposures and genetic predisposition are hypothesized to interact to result in the expression of autoimmune rheumatic diseases such as rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), and systematic autoimmune rheumatic diseases (SARDs) [
Air pollution is a plausible risk factor for autoimmune disease development. Other inhalants such as tobacco smoke and silica are strongly associated with the development of RA, related to their ability to directly interact with alveolar tissue [
Our objective was to identify studies estimating associations between exposure to the air pollutants listed above and the risk of development of select rheumatic diseases. This included inflammatory arthritis conditions such as RA and JIA, as well as SARDs and individual diseases of autoimmune myositis, systemic lupus erythematosus (SLE), scleroderma, and vasculitis.
MEDLINE (1946 to September 2016) and EMBASE (1980 to 2016, week 37) databases were searched using MeSH terms and keywords for rheumatic diseases (RA, SLE, JIA, inflammatory myositis, scleroderma, vasculitis, and SARDs) in relation to exposure to measured air pollutants [
Three authors (Gavin Sun, Glen Hazlewood, and Cheryl Barnabe) independently completed title and abstract and full-text reviews. Studies were included based on the following criteria: assessing the outcome of a rheumatic disease of interest (RA, JIA, SARDs, and individual diseases of autoimmune myositis, SLE, scleroderma, and vasculitis), individual exposure to ambient air pollutants (PM2.5, PM10, SO2, NO2, CO, and O3), and having a case-control, case cross-over, or cohort design. Only English language studies were included. The study had to report risk estimates (any of relative risk (RR), hazard ratio (HR), or odds ratio (OR)) with the corresponding 95% confidence intervals (95% CI) or sufficient data for calculation. Reviews, case reports, mechanism studies, and nonhuman studies were excluded.
Data extraction was performed in duplicate by two authors (Gavin Sun and Cheryl Barnabe). A standard reporting form was developed to extract pertinent information from each study, including the country or region of study, calendar years of study, diagnosis criteria for the rheumatic disease assessed, and the number of patients in case or control groups in each category. The study design and method of assessing air pollutant levels were also extracted. The estimates and their margin of error were extracted. The Newcastle-Ottawa scale [
Our a priori study protocol intention was to perform meta-analysis on eligible studies. Following the full-text review stage, we determined that pooling was not appropriate given the small number of studies and heterogeneity in methods; thus the studies were summarized qualitatively.
A total of 962 unique publications were identified, of which 27 underwent full-text review, with 8 studies included in our summary [
Description of studies included for synthesis.
Disease studied | Author and year | Country or region | Type of study | Sample | Case definition for diagnosis of rheumatic disease | Years of study | Air pollutants studied | Method to determine exposure |
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Rheumatoid arthritis | Chang et al., 2016 [ |
Taiwan | Cohort | Population at risk |
Administrative data, 1 ICD-9-CM code for RA | 2000–2010 | NO2, PM2.5 | Monitoring sites |
De Roos et al., 2014 [ |
British Columbia, Canada | Nested case-control | Controls, |
Administrative data, 2 ICD-9 codes for RA with minimum 1 visit to physician specialist | 1994–2002 | NO2, SO2, PM2.5, PM10, CO, NO, black carbon, ozone | Land use regression method for black carbon, PM2.5, NO2, NO | |
Hart et al., 2013 [ |
Sweden | Case-control | Controls, |
Rheumatologist history and exam | 1996–2008 | NO2, SO2, PM10 | Land use regression | |
Hart et al., 2013 [ |
USA | Cohort | Population at risk, |
Self-report and medical chart review | 1986–2006 | NO2, SO2, PM2.5, PM10 | Land use regression | |
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Systemic autoimmune rheumatic disease | Bernatsky et al., 2016 [ |
Quebec and Alberta, Canada | Cohort | Quebec estimated population at risk, |
Administrative data, 2 ICD-9 codes for SARD or 1 ICD-9 code for SARD by a rheumatologist or 1 instance of hospitalization | Quebec, 1996–2011 |
PM2.5 | Satellite-derived data of exposure levels at location of residence at time of diagnosis |
Bernatsky et al., 2015 [ |
Calgary, Alberta, Canada | Cohort | Not provided | Administrative data, 2 ICD-9 codes for SARD or 1 ICD-9 code for SARD by a rheumatologist or 1 instance of hospitalization | 1993–2007 | PM2.5, NO2 | Land use regression | |
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Juvenile idiopathic arthritis | Zeft et al., 2009 [ |
USA | Cohort (case-crossover) | Cases, |
Clinical registry | 1993–2006 | PM2.5 | Monitoring sites |
Zeft et al., 2014 [ |
USA and Canada | Cohort (case-crossover) | Not mentioned in abstract | Not specified | Not mentioned in abstract | PM2.5 | Selected exposure windows but no mention of extrapolation |
Study selection.
We identified studies in RA (
Four studies included subjects with RA (two case-control studies [
Association between air pollutant exposure and the development of rheumatoid arthritis.
Author | Study design | Association reported | Nitrogen dioxide (NO2) | Fine particulate matter < 2.5 microns (PM2.5) | Fine particulate matter < 10 microns (PM10) | Sulfur dioxide (SO2) |
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Chang et al., 2016 [ |
Cohort |
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Q2, 1.12 (95% CI: 0.83 to 1.52); |
Q2, 1.22 (95% CI: 0.85 to 1.74); |
Not reported | Not reported |
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De Roos et al., 2014 [ |
Nested case-control | OR per IQR |
0.90 (95% CI: 0.85 to 0.96) | 0.92 (95% CI: 0.87 to 0.98) | 0.91 (95% CI: 0.86–0.96) | 0.88 (95% CI: 0.82–0.93) |
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Hart et al., 2013 [ |
Case-control | OR per IQR increase over average |
0.98 (95% CI: 0.90 to 1.07) | Not reported | 0.96 (95% CI: 0.88 to 1.04) | 1.01 (95% CI: 0.93 to 1.09) |
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Hart et al., 2013 [ |
Cohort | HR per IQR range |
0.92 (95% CI: 0.85 to 1.00) | 0.94 (95% CI: 0.86 to 1.04) | 0.92 (95% CI: 0.85 to 0.99) | 0.99 (95% CI: 0.90 to 1.09) |
HR: hazard ratio; IQR: interquartile range; OR: odds ratio.
PM2.5: Quartile 1, <10,760
Bernatsky et al. reported the association between PM2.5 exposure and the odds of prevalent SARDs in case-control studies performed in Quebec and Alberta, Canada [
Two North American studies have explored the association between PM2.5 and JIA. From a patient population in Utah, 338 cases were identified based on a clinical examination by a rheumatologist. Exposure determination was based on monitoring sites data and no-intercept regression models. RR of 1.60 per 10
The four studies in RA and two studies in SARDs were all deemed to be of high quality on the Newcastle-Ottawa scale in domains of selection, comparability, and exposure in the case-control studies and domains of selection, comparability, and outcome for the cohort study. Both studies in JIA were rated at lower quality, related to the case-crossover design selected. A summary of the quality assessment is found in Tables
Newcastle-Ottawa scale for quality of study assessment: case-control studies.
Case-control studies | Manuscript type | Adequate case definition | Representativeness of cases | Selection of controls | Definition of controls | Comparability of cases and controls | Ascertainment of exposure | Consistency ascertainment | Nonresponse rate | Total |
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De Roos, Canada, 2014 (RA) | Full |
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Hart, Sweden, 2013 (RA) | Full |
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Bernatsky, Alberta and Quebec, 2016 (SARD) | Full |
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Bernatsky, Calgary, 2015 (SARD) | Full |
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Zeft, US, 2009 (JIA) | Full |
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0 |
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Zeft, US and Canada, 2014 (JIA) | Abstract |
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0 | 0 |
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0 | 0 |
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For case-control studies, quality was assessed for four domains of selection (case definition, representativeness of cases, selection of controls, and definition of controls), two domains of comparability (study controls for the most important factor and any additional important factor), and three domains of exposure (ascertainment of exposure, same method of ascertainment for cases and controls, and the nonresponse rate). Points are assigned based on specified levels of quality within each domain to a maximum of 9 points.
Newcastle-Ottawa scale for quality of study assessment: cohort studies.
Cohort studies | Representativeness of exposed cohort | Selection of nonexposed cohort | Exposure ascertainment | Measured outcome not present at study onset | Comparability of cohorts | Outcome ascertainment | Sufficient Follow-up to allow outcome to occur | Adequacy of follow-up | Total |
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Chang, Taiwan, 2016 (RA) |
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0 |
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Hart, USA, 2013 (RA) |
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For cohort studies, quality is assessed for four domains of selection (representativeness of exposed cohort, selection of the non-exposed cohort, ascertainment of exposure, and demonstration that the outcome of interest was not present at start of study), two domains of comparability (study controls for the most important factor and any additional important factor), and three domains of outcome (method of assessment of outcome, follow-up period, and adequacy of follow-up of cohorts). Points are assigned based on specified levels of quality within each domain to a maximum of 9 points.
The goal of our research was to synthesize the published literature on associations between air pollution and the development of rheumatic disease. Air pollution has previously been associated with inflammation and other immune-mediated diseases such as inflammatory bowel disease [
There are several possible reasons for the observed findings. Just as peak incidence of RA varies with age, there may be periods of life where the impact of air pollutants has greater influence on subsequent susceptibility to developing autoimmune diseases. Just as younger patients appeared to be more vulnerable to an association between air pollutants and JIA onset in Zeft et al.’s study [
Measurement of exposure is another important consideration when interpreting studies of pollution’s effects on health. Largely, the studies employed place of residence prior to or at diagnosis to determine exposure, without accounting for places where leisure time, occupation, or daily commute might impact risk, resulting in exposure misclassification [
Our systematic review included a broad search strategy in order to ensure complete identification of relevant articles. We did not perform a meta-analysis because of the small number of eligible studies identified and their heterogeneity. Our systematic review serves as a valuable resource that highlights methodological considerations that should be considered in future research studies that explore the relationship between air pollution and immune-mediated diseases.
The existing studies suggest evidence for possible associations of PM2.5 exposure with SARDs development and JIA in younger age cohorts, but the evidence is less clear for links between air pollutant exposures and the development of RA. Additional epidemiologic work is suggested to improve upon existing analysis methods and expand studies of the effects of air pollution on disease phenotype and prognosis. More basic science and translational studies may also help to discover and explain the mechanisms behind progression from pollution related immune stimulation to the formation of antibodies and ultimately to progression of clinically apparent disease.
air pollutio Air Pollution/or Particulate Matter/or Ozone/or Carbon Monoxide/or Nitrogen Dioxide/or Sulfur Dioxide.sh. Or/(1), (2) Arthritis, Rheumatoid/ rheumatoid arthritis.tw. exp Lupus Erythematosus, Systemic/ systemic lupus erythematosus.tw. exp Arthritis, Juvenile/ juvenile idiopathic arthritis.mp. or juvenile arthritis.tw. [mp = title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier] exp Dermatomyositis/or exp Myositis/or exp Polymyositis/ (dermatomyositis or inflammatory my exp Scleroderma, Systemic/or exp Rheumatic Diseases/ (SARD or systemic autoimmune rheumatic disease or scleroderma).mp. or systemic sclerosis.tw. [mp = title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier] exp Systemic Vasculitis/or exp Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/or exp Vasculitis/ vasculitis.tw. (4) or (5) or (6) or (7) or (8) or (9) or (10) or (11) or (12) or (13) or (14) or (15) (3) and (16).
Rheumatoid arthritis
Juvenile idiopathic arthritis
Systematic autoimmune rheumatic diseases
Particulate matter <2.5
Particulate matter <10
Sulfur dioxide
Nitrogen dioxide
Carbon monoxide
Ozone
Systemic lupus erythematosus
Relative risk
Hazard ratio
Odds ratio
95% confidence interval
95% Credible Interval.
Dr. Barnabe is a Canadian Institutes for Health Research New Investigator in Community Based Primary Healthcare.
The authors declare that they have no competing interests.
Gavin Sun, Cheryl Barnabe, Gilaad G. Kaplan, and Sasha Bernatsky designed the study. Gavin Sun and Cheryl Barnabe performed study selection and data extraction. All authors contributed to interpretation of results, drafting of the manuscript, and approving the final manuscript.
This work was supported by the Canadian Institutes for Health Research Team Grant: Challenges in Chronic Inflammation Initiative (PI Dr. B. Eksteen).